Atractylenolide II combined with Interferon-γ synergistically ameliorates colorectal cancer progression in vivo and in vitro by blocking the NF-kB p65/PD-L1 pathway.

Purpose: Atractylodes macrocephala Koidz is a widely used classical traditional Chinese herbal medicine, that has shown remarkable efficacy in cancers. Colorectal cancer (CRC) is the most common malignant tumor globally. Interferon (IFN)-γ, a prominent cytokine involved in anti-tumor immunity that has cytostatic, pro-apoptotic, and immune-stimulatory properties for the detection and removal of transformed cells. Atractylenolides-II (AT-II) belongs to the lactone compound that is derived from Atractylodes macrocephala Koidz with anti-cancer activity. However, whether AT-II combined with IFN-γ modulates CRC progression and the underlying mechanisms remain unclear. The present study aimed to elucidate the efficacy and pharmaceutical mechanism of action of AT-II combined with IFN-γ synergistically against CRC by regulating the NF-kB p65/PD-L1 signaling pathway. Methods: HT29 and HCT15 cells were treated with AT-II and IFN-γ alone or in combination and cell viability, migration, and invasion were then analyzed using Cell Counting Kit-8 (CCK-8) and Transwell assays, respectively. Furthermore, the underlying mechanism was investigated through western blot assay. The role of AT-II combined with IFN-γ on tumor growth and lung metastases was estimated in vivo. Finally, the population of lymphocytes in tumor tissues of lung metastatic C57BL/6 mice and the plasma cytokine levels were confirmed by flow cytometry and enzyme-linked immunosorbent assay (ELISA). Results: AT-II or the combination IFN-γ significantly inhibited the growth and migration abilities of CRC cells in vitro and in vivo. The biological mechanisms behind the beneficial effects of AT-II combined with IFN-γ were also measured and inhibition of p38 MAPK, FAK, Wnt/ß-catenin, Smad, and NF-kB p65/PD-L1 pathways was observed. Moreover, AT-II combined with IFN-γ significantly inhibited HCT15 xenograft tumor growth and lung metastases in C57BL/6 mice, which was accompanied by lymphocyte infiltration into the tumor tissues and inflammatory response inactivation. Conclusions: The results showed that the AT-II in combination with IFN-γ could be used as a potential strategy for tumor immunotherapy in CRC. More importantly, the mechanism by which AT-II suppressed CRC progressions was by inhibiting the NF-kB p65/PD-L1 signal pathway.

Associations between systemic inflammation indicators and nonalcoholic fatty liver disease: evidence from a prospective study.

Background: Although inflammation has been linked to nonalcoholic fatty liver disease (NAFLD), most studies have focused only on a single indicator, leading to inconsistent results. Therefore, a large prospective study that includes a variety of well-documented single and composite indicators of inflammation is needed. This study aimed to thoroughly investigate the potential associations between different systemic inflammatory indicators and NAFLD in the UK Biobank cohort. Methods: After excluding ineligible participants, 378,139 individuals were included in the study. Associations between systemic inflammatory indicators and hepatic steatosis were assessed using multivariate logistic regression. The relationships between systemic inflammatory indicators and nonalcoholic fatty liver disease were analysed using Cox proportional hazards models, and nonlinear associations were investigated using restricted cubic splines. Results: According to the cross-sectional analysis, systemic inflammatory indicators significantly correlated with hepatic steatosis. Over a median follow-up of 13.9 years, 4,145 individuals developed NAFLD. After sufficient adjustment for confounding factors, CRP levels were found to be nonlinearly positively associated with NAFLD risk (P<0.001), representing the strongest correlation among the tested relationships; lymphocyte count and the LMR showed an L-shaped correlation; monocyte count and neutrophil count showed a linear positive correlation (all P< 0.001); and the NLR, PLR, and SII showed a U-shaped correlation (all P<0.001). Conclusions: Multiple systemic inflammatory indicators are strongly associated with the development of NAFLD, and aggressive systemic inflammation management may have a favourable impact on reducing the burden of NAFLD; further randomized controlled studies are needed.

Transcriptome Analysis Reveals the Biocontrol Mechanism of Endophytic Bacterium AM201, Rhodococcus sp., against Root Rot Disease of Atractylodes macrocephala.

Atractylodes macrocephala Koidz (AMK) is a perennial herb from the plant family Asteraceae (formerly Compositae). This herb is mainly distributed in mountainous wetlands in Zhejiang, Sichuan, Yunnan, and Hunan provinces of China. Its medicinal production and quality, however, are severely impacted by root rot disease. In our previous study, endophytic bacterium designated AM201 exerted a high biocontrol effect on the root rot disease of AMK. However, the molecular mechanisms underlying this effect remain unclear. In this study, the identity of strain AM201 as Rhodococcus sp. was determined through analysis of its morphology, physiological and biochemical characteristics, as well as 16S rDNA sequencing. Subsequently, we performed transcriptome sequencing and bioinformatics analysis to compare and analyze the transcriptome profiles of root tissues from two groups: AM201 (AMK seedlings inoculated with Fusarium solani [FS] and AM201) and FS (AMK seedlings inoculated with FS alone). We also conducted morphological, physiological, biochemical, and molecular identification analyses for the AM201 strain. We obtained 1,560 differentially expressed genes, including 187 upregulated genes and 1,373 downregulated genes. We screened six key genes (GOLS2, CIPK25, ABI2, egID, PG1, and pgxB) involved in the resistance of AM201 against AMK root rot disease. These genes play a critical role in reactive oxygen species (ROS) clearance, Ca2+ signal transduction, abscisic acid signal inhibition, plant root growth, and plant cell wall defense. The strain AM201 was identified as Rhodococcus sp. based on its morphological characteristics, physiological and biochemical properties, and 16S rDNA sequencing results. The findings of this study could enable to prevent and control root rot disease in AMK and could offer theoretical guidance for the agricultural production of other medicinal herbs.

Experimental detection of the diamino-pentazolium cation and theoretical exploration of derived high energy materials.

In this work, we realized the detection of diamino-pentazolium cation (DAPZ+) in the reaction solution experimentally and proved it to be meta-diamino-pentazole based on the transition state theory. Quantum chemical methods were used to predict its spectral properties, charge distribution, stability and aromaticity. Considering that DAPZ+ has excellent detonation properties, it was further explored by assembling it with N5-, N3- and C(NO2)3- anions, respectively. The results show a strong interaction between DAPZ+ and the three anions, which will have a positive effect on its stability. Thanks to the high enthalpy of formation and density, the calculated detonation properties of the three systems are exciting, especially [DAPZ+][N5-] (D: 10,016 m·s-1; P: 37.94 GPa), whose actual detonation velocity may very likely exceed CL-20 (D: 9773 m·s-1). There is no doubt that this work will become the precursor for the theoretical exploration of new polynitrogen ionic compounds.

Hierarchical Self-Attention Network for Industrial Data Series Modeling With Different Sampling Rates Between the Input and Output Sequences.

For industrial processes, it is significant to carry out the dynamic modeling of data series for quality prediction. However, there are often different sampling rates between the input and output sequences. For the most traditional data series models, they have to carefully select the labeled sample sequence to build the dynamic prediction model, while the massive unlabeled input sequences between labeled samples are directly discarded. Moreover, the interactions of the variables and samples are usually not fully considered for quality prediction at each labeled step. To handle these problems, a hierarchical self-attention network (HSAN) is designed for adaptive dynamic modeling. In HSAN, a dynamic data augmentation is first designed for each labeled step to include the unlabeled input sequences. Then, a self-attention layer of variable level is proposed to learn the variable interactions and short-interval temporal dependencies. After that, a self-attention layer of sample level is further developed to model the long-interval temporal dependencies. Finally, a long short-term memory network (LSTM) network is constructed to model the new sequence that contains abundant interactions for quality prediction. The experiment on an industrial hydrocracking process shows the effectiveness of HSAN.

Quality Prediction Modeling for Industrial Processes Using Multiscale Attention-Based Convolutional Neural Network.

Soft sensors have been increasingly applied for quality prediction in complex industrial processes, which often have different scales of topology and highly coupled spatiotemporal features. However, the existing soft sensing models usually face difficulties in extracting the multiscale local spatiotemporal features in multicoupled complex process data and harnessing them to their full potential to improve the prediction performance. Therefore, a multiscale attention-based CNN (MSACNN) is proposed in this article to alleviate such problems. In MSACNN, convolutional kernels of different sizes are first designed in parallel in the convolutional layers, which can generate feature maps containing local spatiotemporal features at different scales. Meanwhile, a channel-wise attention mechanism is designed on the feature maps in parallel to get their attention weights, representing the significance of the local spatiotemporal feature at different scales. The superiority of the proposed MSACNN over the other state-of-the-art methods is validated through the performance evaluation in two real industrial processes.

Advanced esophageal cancer with bone metastases: Prognostic biomarkers and palliative treatment.

Esophageal cancer (EC) is a common and devastating tumor of the upper digestive tract. Unfortunately, by the time any symptoms have manifested, the disease has often progressed to an advanced stage and is accompanied by macro- and micrometastases, including in the bones. The treatment of esophageal cancer with bone metastases remains clinically challenging, given the poor prognosis associated with this condition. Effective prognostic biomarkers can help medical staff choose the appropriate operation and treatment plan, that is for most beneficial for making patients. Current treatments for esophageal cancer with bone metastases include pain-relieving drugs, surgical therapy, radiotherapy (RT), chemotherapy (CT, including molecular-targeted drug therapy), endocrine therapy (ET), bisphosphonates (BPs) and interventional therapy. Of these robust measures, radiotherapy has emerged as a particularly promising therapy for bone metastases from esophageal cancer. Substantial progress has been made in radiation therapy techniques since the discovery of X-rays by Roentgen in 1895. In its palliative capacity, the key goals of radiotherapy are to relieve the patients' bone pain and debilitate effects, including relieving spinal cord compression, correcting the spinal deformity and restoring spinal stability. However, it is worth mentioning that RT for esophageal cancer has various side effects. Currently, the available studies focused exclusively on radiotherapy for ECBM are too small to draw any definitive conclusions, and each of these studies has significant limitations. In this review, in addition to the epidemiology described at the beginning, we will explore the current prognostic biomarkers and radiotherapy for esophageal cancer, with a particular focus on those with bone metastases.

Multiscale Feature Fusion and Semi-Supervised Temporal-Spatial Learning for Performance Monitoring in the Flotation Industrial Process.

This article studies the performance monitoring problem for the potassium chloride flotation process, which is a critical component of potassium fertilizer processing. To address its froth image segmentation problem, this article proposes a multiscale feature extraction and fusion network (MsFEFNet) to overcome the multiscale and weak edge characteristics of potassium chloride flotation froth images. MsFEFNet performs simultaneous feature extraction at multiple image scales and automatically learns spatial information of interest at each scale to achieve efficient multiscale information fusion. In addition, the potassium chloride flotation process is a multistage dynamic process with massive unlabeled data. To overcome its dynamic time-varying and working condition spatial similarity characteristics, a semi-supervised froth-grade prediction model based on a temporal-spatial neighborhood learning network combined with Mean Teacher (MT-TSNLNet) is proposed. MT-TSNLNet designs a new objective function for learning the temporal-spatial neighborhood structure of data. The introduction of Mean Teacher can further utilize unlabeled data to promote the proposed prediction model to better track the concentrate grade. To verify the effectiveness of the proposed MsFEFNet and MT-TSNLNet, froth image segmentation and grade prediction experiments are performed on a real-world potassium chloride flotation process dataset.

Episodic Thinking in Alzheimer's Disease Through the Lens of Language: Linguistic Analysis and Transformer-Based Classification.

PURPOSE: Episodic memory decline is a hallmark of Alzheimer's disease (AD) and linked to deficits in episodic thinking directed to the future. We addressed the question whether a deficit in episodic thinking can be picked up directly from connected speech and its detection can be automatized. METHOD: We linguistically classified 2,809 utterances (including embedded clauses in the utterances) from picture descriptions from 70 healthy older controls, 82 people with mild probable AD (pAD), and 46 people with moderate pAD for whether they were episodic, nonepisodic, or "other" (e.g., off-task). Generalized linear regression models were used to investigate how ratios of these categories change in AD, controlling for age, gender, and education. Finally, we applied deep learning technique to explore the feasibility of automating the episodicity analysis. RESULTS: Decline in episodicity significantly distinguished controls from both mild pAD and moderate pAD. Correlation analysis suggested this decline not to be an effect of age, gender, and education but of cognitive ability. The decline was not compensated by an increase of nonepisodic utterances but mainly of off-task expressions. A transformer-based classifier to explore the possibility of automatizing the classification of episodicity achieved a macro F1 score of 0.913 in the ternary classification. CONCLUSION: These results show that a loss of episodicity is an early effect in AD that is manifested in spontaneous speech and can be reliably measured by both humans and machines.

Neuroprotective effect of 1,25­dihydroxyvitamin D3 against hyperoxia­induced brain injury in premature rats.

Studies have shown that vitamin D plays a crucial role in brain development, brain metabolism and neuroprotection. There is little evidence for the neuroprotective effect of 1, 25­dihydroxyvitamin D3 (1,25­(OH)2D3) on various brain injury models. The aim of this study was to investigate the neuroprotection effect of 1,25­(OH)2D3 against hyperoxia­induced brain injury in premature rats. Sprague­Dawley rats were exposed to 95% oxygen or room air for 24 h and treated with 1,25­(OH)2D3 or normal saline for 14 consecutive days. The histopathological changes of optic chiasma tissue were observed by hematoxylin­eosin staining. Immunohistochemistry, qRT­PCR, and western blot were performed to detect the expression of integrin­ß1 and yes­associated protein (YAP) in the organization of the optic chiasm. Histopathological sections of optic chiasma showed visible optic nerve swelling, expanded nerve fiber space, uneven staining, obvious oligodendrocyte proliferation and disordered cell arrangement accompanied by inflammatory cell infiltration and exudation after 7 days and 14 days of hyperoxia exposure. The hyperoxia group treated with 1,25­(OH)2D3 were showed improvement of brain injury with reduced inflammatory exudation, uniform nerve fiber staining and less obvious oligodendrocyte proliferation. Immunohistochemical staining, qRT­PCR and western blot indicated that 1,25­(OH)2D3 treatment upregulated the expression of integrin­ß1 and YAP in the hyperoxia group on day 7. However, the expression of YAP was significantly increased compared with control group and treatment with 1,25­(OH)2D3 reduced the expression of YAP in the hyperoxic group on day 14. 1,25­(OH)2D3 may regulate the expression of integrin­ß1 and YAP to alleviate hyperoxia­induced brain injury in premature rats.

Causal associations between gut microbiota and sepsis: A two-sample Mendelian randomization study.

BACKGROUND: Targeting the gut microbiota may become a new therapeutic to prevent and treat sepsis. Nonetheless, the causal relationship between specific intestinal flora and sepsis is still unclear. METHODS: A two-sample Mendelian randomization study was performed using the summary statistics of gut microbiota from the largest available genome-wide association study (n = 18,340). The summary statistics of sepsis were obtained from the UK Biobank (n = 486,484). Inverse-variance weighted, weighted median and MR-Egger were used to examine the causal association between gut microbiota and sepsis. Cochrane's Q test, MR-Egger intercept test, MR-PRESSO Global test and Rucker's Q'-test were used for sensitivity analyses. The leave-one method was used for testing the stability of MR results, and Bonferroni-corrected was used to test the strength of the causal relationship between exposure and outcome. RESULTS: Nine intestinal microflora were found causally associated with sepsis, and 11 intestinal microflora were causally associated with 28-day death in sepsis. Among them, Order Victivallales had a strong causality with lower risk of sepsis (OR = 0.86, 95% CI: 0.78-0.94, p = .00165) and lower 28-day mortality of sepsis (OR = 0.68, 95% CI: 0.53-0.87, p = .00179) after Bonferroni-corrected test. No pleiotropy was detected. CONCLUSIONS: Through the two-sample MR analysis, we identified the specific intestinal flora that had a causal relationship with the risk and prognosis of sepsis at the level of gene prediction, which may provide helpful biomarkers for early disease diagnosis and potential therapeutic targets for sepsis.

Multi-aspect simulation insight on thermolysis mechanism and interaction of NTO/HMX-based plastic-bonded explosives: a new conception of the mixed explosive model.

Reactive molecular dynamics (RMDs) calculations were used to determine, for the first time, the process of thermolysis of the mixed explosives, including 3-nitro-1,2,4-triazol-5-one (NTO) and octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazoline (HMX). Significantly, this is the first time that a layered model for mixed explosives, which is an extreme innovation of mixed explosive models was adopted. It is shown that a large amount of NO2 in the HMX and OH groups generated by the decomposition of HNO2 has a favorable effect on the thermolysis of NTO, as further validated by a reduction in the activation energy of NTO/HMX. The amount of H2O and N2 in the resulting products increased significantly, but the amount of NH3 changed slightly. The analysis results correspond to the change in chemical bonds. Whenever there is an increase in temperature, the time for the maximum number of clusters to appear is shortened accordingly. In addition, the acidity of NTO has been considered. An independent gradient model based on Hirshfeld partition (IGMH) and atoms in molecule (AIM) analysis of NTO/HMX was implemented. The relatively strong hydrogen bonds indicate that HMX can inhibit the acidity of NTO and is beneficial for the wide application of NTO/HMX-based plastic-bonded explosives (PBXs).

Semi-supervised deep embedded clustering with pairwise constraints and subset allocation.

Semi-supervised deep clustering methods attract much attention due to their excellent performance on the end-to-end clustering task. However, it is hard to obtain satisfying clustering results since many overlapping samples in industrial text datasets strongly and incorrectly influence the learning process. Existing methods incorporate prior knowledge in the form of pairwise constraints or class labels, which not only largely ignore the correlation between these two supervision information but also cause the problem of weak-supervised constraint or incorrect strong-supervised label guidance. In order to tackle these problems, we propose a semi-supervised method based on pairwise constraints and subset allocation (PCSA-DEC). We redefine the similarity-based constraint loss by forcing the similarity of samples in the same class much higher than other samples and design a novel subset allocation loss to precisely learn strong-supervised information contained in labels which consistent with unlabeled data. Experimental results on the two industrial text datasets show that our method can yield 8.2%-8.7% improvement in accuracy and 13.4%-19.8% on normalized mutual information over the state-of-the-art method.

Theoretical study on the influence of different solvents on the growth morphology of 3,4-bis(3-nitrofurazan-4-yl)furoxan (DNTF).

CONTEXT: 3,4-bis(3-nitrofurazan-4-yl)furoxan (DNTF) is a new energetic compound with high energy and high density, and it is an important component of propellant and melt cast explosive. In order to study the effect of solvent on the growth morphology of DNTF, the growth plane of DNTF in vacuum is predicted by attachment energy (AE) model, and then the modified attachment energy of each growth plane in different solvents is calculated by molecular dynamics simulation. The morphology of crystal in solvent is predicted by modified attachment energy (MAE) model. The factors affecting crystal growth in solvent environment are analyzed by mass density distribution, radial distribution function and diffusion coefficient. The results show that the growth morphology of crystal in solvent is not only related to the adsorption strength of solvent to crystal plane, but affected by the attraction of crystal plane to solute. The hydrogen bond plays an important role in the adsorption strength between solvent and crystal plane. The polarity of solvent has a great influence on the crystal morphology, and the interaction between the solvent with stronger polarity and the crystal plane is stronger. The morphology of DNTF in n-butanol solvent is closer to spherical, which can effectively reduce the sensitivity of DNTF. METHODS: The molecular dynamics simulation is carried out under the COMPASS force field of Materials Studio software. Gaussian software is used to calculate the electrostatic potential of DNTF at B3LYP-D3/6-311 + G (d, p) theoretical level.

Three New Steriodal Saponins from the Rhizomes of Tupistra chinensis Baker.

The phytochemical constituent investigation on the 70 % ethanol extract of the rhizomes of Tupistra chinensis Baker resulted in the isolation of three new steroidal saponins which were named tuchinosides A-C (1-3). Their structures were determined by extensive spectrum analysis and chemical evidence, especially 2D NMR and HR-ESI-MS techniques. In addition, the cytotoxicity of compounds 1-3 against several human cancer cell lines was evaluated.

Macrophage-Targeted Dextran Sulfate-Dexamethasone Conjugate Micelles for Effective Treatment of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic, systemic immune disease that causes joint affection and even disability. Activated macrophages play an important role in the pathogenesis and progression of RA by producing pro-inflammatory factors. The use of dexamethasone (DXM) is effective in relieving the intractable pain and inflammatory progression of RA. However, long-term use of DXM is strongly associated with increased rates of diabetes, osteoporosis, bone fractures, and mortality, which hinders its clinical use. In this study, the dextran sulfate-cisaconitic anhydride-dexamethasone (DXM@DS-cad-DXM) micelles were prepared to treat RA by selectively recognizing scavenger receptor (SR) on the activated macrophages. The potent targeting property of DXM@DS-cad-DXM micelles to SR was by fluorescence microscope. Additionally, the effective accumulation and powerful anti-inflammatory activity of DXM@DS-cad-DXM micelles were observed in the inflamed joints of adjuvant-induced arthritis (AIA) rats after intravenous administration. Overall, DXM@DS-cad-DXM micelles are a potentially effective nanomedicine for targeted therapy of RA.

Steriodal saponins from the rhizomes of Tupistra chinensis Baker.

Chemical constituent investigation on the n-BuOH extract of the rhizomes of Tupistra chinensis Baker leads to the isolation of ten compounds including eight undescribed furostanol saponins, tupischinosides A - H, and two known ones. The structures of isolated compounds were determined by extensive spectral analysis and chemical evidences. Interestingly, tupischinosides A and B, C and D, E and F, G and H were identified as four pairs of epimers. The cytotoxicity of tupischinosides A - H against human cancer cell lines U87, SHG44, U251, LN229 and HepG-2 was evaluated by CCK-8 method. As a result, tupischinosides A and C exhibited significant proliferation inhibitory effect on the tested cancer cells. On the contrary, the corresponding epimers, tupischinosides B and D, which only differ in the configuration of C-23 didn't exhibit any cytotoxicity to cancer cells. These results indicated that the stereochemistry of C-23 was crucial to the activity of the compounds.

Umbilical Cord Wharton's Jelly-Derived Mesenchymal Stem Cells Inhibit the TGF-ß1 Pathway in Hepatic Fibrosis Rats Through a Paracrine Regulation Process.

BACKGROUND: The aim is to verify the therapeutic effect and possible mechanism of human umbilical cord Wharton's jelly-derived transplantation of mesenchymal stem cells (UMSCs) on CCl4-induced hepatic fibrosis rats through in vivo studies and to explore the regulatory mechanism of UMSCs on fibrosis of hepatic stellate cells (HSCs) through in vitro experiments. METHODS: In vivo experiment: Rats were randomly divided into blank control group and hepatic fibrosis group. During the entire trial, the blank control group received subcutaneous injection of normal saline, while in the hepatic fibrosis group received injections of 50% CCl4-olive oil subcutaneously for 10 weeks to establish the rat model of liver fibrosis. Hepatic fibrosis rats were then randomly and evenly divided into umbilical cord mesenchymal stem cell (UMSC) group, bone marrow mesenchymal stem cell (BMSC) group, UMSC-culture medium (CM) group, and control group. Rats in each group were infused with the following substances through the caudal vein as follows: 1 mL UMSCs (2 × 106/mL) in UMSC group, 1 mL BMSCs (2 × 106/mL) in BMSC group, 1 mL UMSCs-CM in CM group, and 1 mL saline in control group. Rats of each group were closely observed (weight, hair condition, activity, appetite, diarrhea, etc.), venous blood samples were collected, the number of white blood cells and lymphocytes were measured, and liver function indicators (ALT, AST, TBIL, ALB) were determined. Three weeks later, rat liver specimens were taken, HE stained, pathological changes were examined and quantified. In vitro experiments: HSCs were seeded in 6-well plates at 1.0 × 105/mL, with a serum-free medium for 24 hours. Then, 2 mL of UMSCs-CM was added in the study group, while an equal amount of complete medium was added to the control group. RT-PCR was used to detect TGF-ß1, Collagen-I, TIMP-2 mRNA expression in HSCs, and western blot was used to detect TGF-ß1 protein expression in HSCs. RESULTS: In vivo experiment: Compared with the control group, after the transplantation, the activity status (weight, spirit, appetite, movement, hair, diarrhea, etc.) of rats in the UMSC group, BMSC group, and CM group were improved. The liver function indexes of these groups, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL) were significantly decreased (p < 0.05), while albumin (ALB) levels were mildly but not significantly increased (p > 0.05). The Knodell score (reflecting the degree of liver inflammation) and Chevallier score (reflecting the degree of liver fibrosis) of liver specimens in pathological examination were also significantly reduced, and the difference in the quantitative scores of those indexes was statistically significant (p < 0.05). There was no statistically significant difference in the number of venous white blood cells and lymphocytes, liver function indexes (ALT, AST, TBIL, ALB), Knodell score, and Chevallier score of liver samples among the UMSC group, BMSC group, and CM group. In vitro experiments: After treatment with UMSCs-CM, the expression of TGF-ß1, Collagen-I, and TIMP-2 mRNA in HSCs was significantly down-regulated compared with that of the control group (treated with complete medium), and it gradually decreased with the extension of the treatment time. Compared with the control group, the expression of TGF-ß1 protein in the HSCs of the experimental group was down-regulated, and this effect was time-dependent, specifically, the control group (2.49 ± 0.43) > the experimental group at 48 hours (1.98 ± 0.26) > the experimental group at 72 hours (1.62 ± 0.20) (F = 7.796, p < 0.05). CONCLUSIONS: In rats with liver fibrosis, transplantation of UMSCs can improve liver function and reduce the inflammatory activity and fibrosis of the liver, possibly through the paracrine mechanism. UMSCs inhibit HSCs fibrosis through a paracrine mechanism, which is time-dependent, possibly by targeting TGF-ß1 and its downstream gene products.

Carboxypeptidase Vitellogenic-Like Promotes the Proliferation and Metastasis of Osteosarcoma through the TGF-ß/Smad Signaling Pathway.

OBJECTIVE: This research explored the biological role and underlying mechanisms of carboxypeptidase vitellogenic-like (CPVL) in the progression of osteosarcoma. METHODS: Through mining of microarray data from the GEO database and utilization of qRT-PCR and Western blot analyses, CPVL expression in osteosarcoma tissues and cells was evaluated. RNA interference and lentiviral transduction techniques were applied to edit the CPVL gene. RNA-seq was used to screen for the downstream target genes of CPVL. RESULTS: In both osteosarcoma biopsy samples and cell lines, the expression of CPVL was abnormally higher than that in normal cells or osteoblasts. CPVL silencing notably inhibited the proliferative activity of osteosarcoma cells, whereas CPVL overexpression had the opposite effect. CPVL silencing had potent tumor-suppressive ability in a xenograft osteosarcoma model in nude mice. CPVL silencing significantly suppressed osteosarcoma cell migration, invasion and EMT, whereas CPVL overexpression accelerated these events. Downstream genes related to the occurrence and development of osteosarcoma, including TGF-ß/Smad signaling pathway molecules (TGF-ß2, TGF-ßR1, Smad2/3, and Smad5), were suppressed by CPVL silencing. CONCLUSIONS: High CPVL expression in osteosarcoma not only promoted tumor growth but also induced the EMT process through the TGF-ß/Smad signaling pathway. CPVL may be a new antitumor therapeutic target for osteosarcoma.

Therapeutic effects of multidisciplinary individualized treatment for COVID-19 patients: the experience of a supporting medical team in Wuhan.

Background: The sudden outbreak of coronavirus disease 2019 (COVID-19) has brought people around the world into an abyss of suffering. At that time, there were no clear and effective means for the treatment of the virus. We prepared a medical team consisted of specialists in critical care, respiratory diseases, infections, gastroenterology, endocrinology, cardiology, cerebrovascular diseases, nephrology, rehabilitation, psychology, and nutrition. This study shared our multidisciplinary treatment experience in treating patients with COVID-19. Methods: Patients with positive SARS-CoV-2 swab test were divided into three groups: ordinary cases, severe cases and critical cases. Every patient received the multi-disciplinary comprehensive and individualized tailored treatment based on the specific situation of each patient. Patients' medical records, epidemiological, clinical, laboratory, radiological characteristics, Borg dyspnea score, Barthel index, self-rating anxiety scale (SAS) as well as treatment and outcome data were analyzed. Results: The mean age of the 90 patients was 61.88±15.25 years. Some patients without underlying disease had developed comorbidities such as hyperglycemia (24, 26.67%) and hypertension (9, 10%). With multidisciplinary individualized treatment, the patients' albumin level and Barthel index score increased significantly, while glucose level, blood pressure, and Nutrition Risk Screening 2002 (NRS-2002), Borg scale, and SAS values significantly decreased at discharge. The in-hospital mortality rate was 4.44%. However, there was still a gap in Nutrition Risk Screening, Borg dyspnea score and Barthel index between the critical cases and the ordinary and severe cases at discharge. We observed that the patients with more severe disease had significantly higher age, rates of hypertension, and mortality. The median hospitalization time of discharged patients was 19 days [interquartile range (IQR), 9.0-20.0 days]. Conclusions: Multidisciplinary collaboration and individualized treatment could effectively improve the general status of patients with different severity of COVID-19.